The use of an essentially pure opiate receptor antagonist in the treatment of several diseases has already been disclosed in patents in which I am named as an inventor. In U.S. Pat. No. 4,888,346, issued Dec. 19, 1989, the treatment was for the acquired immune deficiency syndrome (or AIDS) in any of its known states, including AIDS-related complex. In U.S. Pat. No. 5,013,739, issued May 7, 1991, the disease treated was chronic fatigue syndrome while in U.S. Pat. No. 5,346,900, issued Oct. 18, 1994, the disease was chronic herpes virus infections. In the latter patent, examples of treatment of multiple sclerosis was also disclosed.
For the treatment of all these diseases, the amount of the essentially pure opiate receptor antagonist was required to be at a quite low level corresponding in results to those obtained by the administration of Naltrexone at a dosage level of from 1.0 mg. to 10 mg., preferably at a dosage level of 1.0 mg. to about 5 mg., and most preferably up to about 3.0 mg. At dosage levels above about 10 mg., not only were the desired therapeutic results not obtained but the effect of the treatment appeared to be negative in acerbating the disease.
I have now discovered that administration of an essentially pure opiate receptor antagonist gives desirable and beneficial therapeutic results in the treatment of a group of closely related malignancies known as lymphoproliferative syndrome, which includes malignant lymphoma, chronic lymphocytic leukemia, Hodgkin's disease (or Hodgkin's lymphoma), and non-Hodgkin's lymphoma. As the generic name suggests, these diseases are characterized by the multiplication or proliferation of tissue of the lymphatic system, especially lymphocytes (cells) produced in the lymph nodes. Lymphocytes are important components of the human immune response system and upon exposure to a foreign antigen in the human body naturally proliferate or multiply to combat the antigen. In this group of malignancies, the proliferation goes out of control, resulting in an abnormal level of lymphocytes in the blood stream, enlargement of the lymph nodes due to accumulation of the lymphocytes there, and other symptomatic characteristics.
In the past, these diseases were generally treated by radiology and chemotherapy often employing a combination of antineoplastic agents. I have discovered that the lymphoproliferative syndrome can respond to an entirely different therapeutic approach involving the administration of essentially pure opiate receptor antagonists at the same relatively low quantitative level that was found useful for the treatment of the disorders disclosed in the above-specified patents despite the totally different nature of the earlier diseases which did not involve any malignant behavior.
It is not possible to provide any coherent rationale for the therapeutic effectiveness of an essentially pure opiate receptor antagonist against the diseases falling within the lympholiferative syndrome. Indeed, any therapeutic activity of these antagonists for the lymphoproliferative syndrome would appear from general principles of immune action to be highly unlikely if not entirely out of the question. It is generally believed that the immunocompetent action of lymphocytes arises out of some surface structural feature, usually called "receptor", that is capable in some way of "recognizing", perhaps by "capture", some structural feature of an invading foreign antigen. This "recognition" mechanism, whatever its nature, initiates the production of antibodies effective against the particular antigen. Even assuming that lymphocytes have receptors for opiates, it is quite puzzling that blocking of these receptors by an opiate antagonist would in some way interfere with whatever is the causative factor or factors in lymphatic cancers.
If an occurrence of the lymphoproliferative syndrome could be traced strongly to viral or bacterial action and if such action is assumed to involve receptor sites on lymphocytes, one could possibly theorize that an opiate receptor antagonist might be preferentially blocking such sites and preventing any connection with viral or bacterial particles. However, viral and bacterial sources are usually accepted as having a limited association with any disease of the lymphoproliferative syndrome and this theory thus could hardly apply to all of the diseases of this syndrome.
In any case, while such an association might explain how administration of an opiate receptor antagonist could reduce the likelihood of the original initiation of the malignancy, it would not explain how such administration could provide a therapeutic action after the malignancy has progressed to the point of treatment. It is true for lymphatic cancers as for all cancers that at the time diagnosis is possible, the cancer is necessarily at a well-developed, if not "advanced", stage of development. Receptor site preclusion cannot therefore explain an interference with a malignant proliferation of the lymphocytes. This is particularly true since the presence of the opiate receptor antagonist does not appear to block normal proliferation of the lymphocytes in the system and their differentiation into B- and T-type cells as is essential to a viable immune function.
McLaughlin et al have disclosed in U.S. Pat. No. 4,689,332; among others, that opiate receptor antagonists. exemplified by Naltrexone and Naloxone, when administered to a variety of living organisms, including tissue and cells, can exert either a growth accelerating or a growth inhibiting effect dependent upon the length of time the opiate receptor sites of the organism are "completely and continuously" blocked or occupied by the antagonist. Specifically, a growth accelerating or promoting action occurs with blockage for a period of at least 12 hours per day, as can be achieved with a dosage of at least about 10 mg. and preferably about 20 mg. per day, whereas a growth inhibiting action occurs with blockage for only a period of about 2 to 12 hours per day, as can be achieved with a dosage of less than 10 mg. down to about 0.1 mg. per day.
The growth accelerating embodiment is said to be effective "to proliferation, migration, and differentiation of certain specific cells or tissue, including organ tissues, neural tissue, bone marrow, red blood cells, lymphocytes, liver cells, etc." (See patent, col. 9, lines 15-25.) This disclosure, however, is silent as to whether these any of these same "cells or tissues" can be subject to the growth inhibiting embodiment, the focus of the inhibiting embodiment disclosure paralleling the above excerpt being on weight loss of the organism as a whole. (See col. 9, lines 32-45 and col. 10, lines 45-59.)
In addition, the growth inhibiting aspect is described as "related to the prevention, treatment and control of cancer" (see col. 10, line 60--col. 11, line 47), the essential disclosure in this connection being as follows; "The action of the compounds of the invention can be employed to terminate the rapid growth patterns of cancer and related abnormalities. It should be understood, that a regime of the present compounds cannot dissipate or reduce a tumor mass or other metastasized growth. These compounds can only terminate the growth of the abnormal cells and inhibit the continued growth thereof. However, by preventing tumor growth to continue [sic], i. e. reducing the tumor burden, the body's own defense mechanism, i. e. the immune system, has the opportunity to rid the body of the cancerous growth whether benign or malignant. This aspect of the invention is particularly significant in light of early diagnostic techniques which do reduce tumor size, or with procedures for tumor excision. Moreover, naloxone, naltrexone, or the other related compounds can be administered as a prophylaxis to human or animal subjects who may be exposed to potentially carcingenic [sic] agents."
The only cancer specifically identified for treatment in McLaughlin et al. patent is neuroblastona in mice, as illustrated by specific examples 2, 3, and 5, the only examples concerned with cancer. Neuroblastoma is a rather rare and special type of cancer, occurring in the sympathetic autonomous nervous system, i. e. mainly the nerves of the spinal column, and is essentially limited to young children up to about 10 years of age. Evidence has been reported that neuroblastoma is peculiarly susceptible to natural immunobiological resistance. According to "IMMUNOBIOLOGY POR THE CLINICIAN" by Barber, Copyright 1977, John Wiley & Sons, the lymphocytes of disease-free mothers of young neuroblastoma patients have the capacity to kill neuroblastoma cells extracted from their diseased children but had no effect on normal tissue cells or tumor cells of other than neuroblastoma and that lymphocytes of siblings of such patients also were able to kill neuroblastoma cells of the patients. (Cf p. 69). The same text states (at p. 102) that incidence of neuroblastoma nodules found by autopsy is "40-50 times greater" than the overall incidence of clinically diagnosed neuroblastoma. This obviously suggests that a competent immune system exerts a strong controlling action on neuroblastoma which is found in few other kinds of cancers.
While there is a tendency among the general public (and even the often equally uninformed media) to generalize between all "cancers", (a conception which unfortunately appears to be shared by McLaughlin et al) "cancer" is, in fact, a collection of many distinct malignancies, each with its unique characteristics, behavior, and treatment response (which is one reason for the tortuously slow progress in the treatment of "cancer"), and this individualistic nature is especially applicable in the case of neuroblastoma. One cannot, therefore, reasonably extrapolate from the response of neuroblastoma to a given prophylaxis to a supposition that an entirely different type of "cancer" will exhibit the same response and this conclusion is particularly valid in the case of lymphoproliferative malignancies.
As already noted above, lymphocytes are at least a core component, if not the keystone, of the body's immune system which is an important, if not the principal, mechanism by which the body attacks and controls cancers generally. It is the lymphocytes, or their derivatives, which recognize the foreign antigenic nature of cancer cells or of antibodies associated therewith and attack the cancer cells. The route set forth by McLaughlin et al. for controlling "cancer" by their treatment, as quoted above, does not make sense when it is the lymphocytes themselves that are malignant. How can proliferation of malignant lymphocytes be inhibited without at the same time inhibiting the natural proliferation of normal lymphocytes essential to effective functioning of the immune system? Further, if the object of the treatment is, as stated, to reduce the extent of the cancer to a degree within the capacity of the immune system (lymphocytes) to control, how does an active "normal" lymphocyte recognize a malignant lymphocyte?.
For at least these reasons, therefore, the discovery that essentially pure opiate receptor antagonists, such as naltrexone or naloxone, exert therapeutic action against the lymphoproliferative syndrome is believed to be unexpected if not remarkable.
The diseases usually identified within the lymphoproliferative syndrome have been previously identified and their symptoms and other characteristics can be found in abbreviated form in any medical encyclopedia, such as "Miller-Keane Encyclopedia & Dictionary of Medicine, Nursing, & Allied Health", 5th Edition, 1992, W. B. Saunders Co. or in more expanded form in any medical text, such as for example "Cecil Essentials of Medicine", by Andreoli etal, Copyright 1986 by W. B. Saunders Co. At present, the four diseases identified are considered to constitute the lymphoproliferative syndrome but if other diseases should be characterized by excessive proliferation of lymphocytes, they too would respond to the present therapy and should be deemed within the scope of the invention.
Similarly, while Naltrexone and Waloxone are presently the only essentially pure opiate receptor drugs known to have received government approval for administration to humans, if other drugs exist or should be developed exhibiting the same preferential or selective affinity for Mu over Delta opiate receptor sites, they too should be effective for purposes of the present method and are within the scope of the invention. For more details of this selective or preferential action, reference may be had to U.S. Pat. No. 5,013,739, the relevant portions of which, in particular col. 5, line 17--col. 6, line 25, are incorporated by reference.
Similarly, while the dosage levels have been briefly specified above, more complete information as to dosage level which is applicable to the present invention, is given in the same -739 U.S. patent, especially col. 6, line 59--col. 7, line 17, which is incorporated by reference. In as much as Naltrexone is available in a form suitable for oral administration and is recognized to be effective when so administered, it is preferred that the Naltrexone be utilized as the opiate antagonist and be administered orally, but where effective other administration routes are, in principle, not precluded and can be employed. Naloxone, on the other hand, has not generally proven to be effective when administered orally; it is available in a form suitable for injection and is better administered by injection,
It is also preferred that administration take place in the evening hours, and particularly at bedtime, since the action of the antagonist appears to develop more strongly when the patient is sleeping and at rest.